The Mitochondrial Transacylase, Tafazzin, Regulates AML Stemness by Modulating Intracellular Levels of Phospholipids

Seneviratne, Ayesh K.; Xu, Mingjing; Henao, Juan J. Aristizabal; Fajardo, Val A.; Zhou, Hao; Voisin, Véronique; Xu, Gang; Hurren, Rose; Kim, S.; MacLean, Neil; Wang, Xiaoming; Gronda, Marcela; Jeyaraju, Danny V.; Jitkova, Yulia; Ketela, Troy; Mullokandov, Michael; Sharon, David; Thomas, Geethu Emily; Chouinard‐Watkins, Raphaël; Hawley, James R.; Schafer, Caitlin; Yau, Helen Loo; Khuchua, Zaza; Aman, Ahmed; Al‐awar, Rima; Gross, Atan; Claypool, Steven M.; Bazinet, Richard P.; Lupien, Mathieu; Chan, Steven M.; Carvalho, Daniel D. De; Minden, Mark D.; Bader, Gary D.; LeBlanc, Paul J.; Schimmer, Aaron D.

doi:10.1016/j.stem.2019.04.020

Cited by 15 publications

(13 citation statements)

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“…Furthermore, LACTB‐mediated tumour suppression by increasing mitochondrial lipid metabolism [ 40 ]. Finally, acute myeloid leukaemia (AML) cells lacking PSD failed to form tumours [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis

et al. 2021

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SMAC/Diablo, a pro‐apoptotic protein, yet it is overexpressed in several cancer types. We have described a noncanonical function for SMAC/Diablo as a regulator of lipid synthesis during cancer cell proliferation and development. Here, we explore the molecular mechanism through which SMAC/Diablo regulates phospholipid synthesis. We showed that SMAC/Diablo directly interacts with mitochondrial phosphatidylserine decarboxylase (PSD) and inhibits its catalytic activity during synthesis of phosphatidylethanolamine (PE) from phosphatidylserine (PS). Unlike other phospholipids (PLs), PE is synthesized not only in the endoplasmic reticulum but also in mitochondria. As a result, PSD activity and mitochondrial PE levels were increased in the mitochondria of SMAC/Diablo‐deficient cancer cells, with the total amount of cellular PLs and phosphatidylcholine (PC) being lower as compared to SMAC‐expressing cancer cells. Moreover, in the absence of SMAC/Diablo, PSD inhibited cancer cell proliferation by catalysing the overproduction of mitochondrial PE and depleting the cellular levels of PC, PE and PS. Additionally, we demonstrated that both SMAC/Diablo and PSD colocalization in the nucleus resulted in increased levels of nuclear PE, that acts as a signalling molecule in regulating several nuclear activities. By using a peptide array composed of 768‐peptides derived from 11 SMAC‐interacting proteins, we identified six nuclear proteins ARNT, BIRC2, MAML2, NR4A1, BIRC5 and HTRA2 Five of them also interacted with PSD through motifs that are not involved in SMAC binding. Synthetic peptides carrying the PSD‐interacting motifs of these proteins could bind purified PSD and inhibit the PSD catalytic activity. When targeted specifically to the mitochondria or the nucleus, these synthetic peptides inhibited cancer cell proliferation. To our knowledge, these are the first reported inhibitors of PSD acting also as inhibitors of cancer cell proliferation. Altogether, we demonstrated that phospholipid metabolism and PE synthesis regulated by the SMAC‐PSD interaction are essential for cancer cell proliferation and may be potentially targeted for treating cancer.

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Section: Discussionmentioning

confidence: 99%

SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis

et al. 2021

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“…Recent work indicated that leukemic stem cells might be sensitive to OXPHOS inhibition [24][25][26][27] . It was shown that distinct subtypes of AML are particularly sensitive to mubritinib, which targets electron chain complex I activity 49 .…”

Section: Discussionmentioning

confidence: 99%

“…HSCs maintain low levels of reactive oxygen species (ROS) in order to maximize their lifespan 21 , and also leukemic stem cells have been proposed to be glycolytic and maintain a ROS low state 13,22 , although this might also depend on mutational status 23 . Recent work also indicated that leukemic stem cells might in fact be sensitive to OXPHOS inhibition [24][25][26][27] , an observation mimicked in healthy HSCs where complete removal of respiratory chain activity resulted in reduced HSC function 28 .…”

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confidence: 99%

The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia

et al. 2022

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Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients. Here, we show that Pyruvate dehydrogenase kinase 1 (PDK1) acts as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). PDK1low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1high AMLs however are OXPHOSlow, wild type for FLT3 and NPM1, and are enriched for stemness signatures. Metabolic states can even differ between genetically distinct subclones within individual patients. Loss of PDK1 activity releases glycolytic cells into an OXPHOS state associated with increased ROS levels resulting in enhanced apoptosis in leukemic but not in healthy stem/progenitor cells. This coincides with an enhanced dependency on glutamine uptake and reduced proliferation in vitro and in vivo in humanized xenograft mouse models. We show that human leukemias display distinct metabolic states and adaptation mechanisms that can serve as targets for treatment.

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“…The mechanism here was found in the PS decarboxylase (PISD), which converts PS to PE in the IM. As recombinant PISD binds preferentially to cardiolipin, and knockdown of tafazzin decreased protein levels of PISD, it was concluded that reduced PS conversion contributes to the phospholipid shift in AML cells 66 . Furthermore, decreased levels of plasmalogens in heart, liver, kidney, brain and lymphocytes are documented in the BTHS mouse model 68 .…”

Section: The Role Of Tafazzin In Cardiolipin Remodelingmentioning

confidence: 99%

“…This also explains that tafazzin activity supports different CL compositions in different tissues. In contrast to its role in maintaining CL with unsaturated fatty acids in heart tissue, tafazzin knockdown in acute myeloid leukemia (AML) cells produced CL acyl species with more than 5 double bonds and longer chains 66 …”

Section: The Role Of Tafazzin In Cardiolipin Remodelingmentioning

confidence: 99%

Mechano‐energetic aspects of Barth syndrome

Dudek

Maack

2021

J of Inher Metab Disea

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Energy‐demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation‐contraction coupling, calcium (Ca2+) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca2+ influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca2+ uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies.

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The Mitochondrial Transacylase, Tafazzin, Regulates AML Stemness by Modulating Intracellular Levels of Phospholipids

Cited by 15 publications

References 0 publications

SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis

SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis

The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia

Mechano‐energetic aspects of Barth syndrome

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